Huntington's disease (HD) is a relentlessly progressive autosomal dominant neurodegenerative disorder characterized by the development of involuntary movements, cognitive decline, and psychiatric illness (1). This polyglutamine disorder arises from a CAG trinucleotide-repeat expansion mutation in the coding region of the huntingtin (Htt) gene encoding an extended polyglutamine (polyQ) tract. Recent studies by our laboratory and others have shown that the mitochondrial dysfunction and metabolic deficits in HD result from transcriptional dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1) (2, 3). As a transcriptional regulator, PGC-1 positively modulates several nuclear receptor transcription factors including the three Peroxisome Proliferator-Activated Receptor (PPAR) isoforms, , ?, and . Of these, PPAR is the most abundantly expressed subtype in the central nervous system (CNS), although its functional relevance in this tissue has not been well defined (4, 5). With the discovery that retinoic acid binds to PPAR to mediate its previously well-documented pro-survival effects (6, 7), PPAR may be responsible for promoting a variety of survival / repair processes in neurons (8-10). Multiple components of the PPAR signaling transcriptional pathway have been elucidated in non-neuronal systems (6, 7). Pharmacologic (26) and genetic (27,28) activation of PPAR increases expression of genes involved in energy metabolism and mitochondrial biogenesis. The role of PPAR in neuronal function has not been well-defined, despite being expressed at levels higher than those in muscle (29). In Aim 1, I will test the hypothesis that polyglutamine-expanded huntingtin protein interferes with PPAR -mediated gene transcription, a perturbation that may contribute to the molecular pathology of Huntington's disease. In Aim 2, I will perform experiments in vitro and in vivo to test the hypothesis that enhancing the PPAR signaling pathway will ameliorate transcriptional dysfunction and neuronal degeneration seen in HD. By elucidating the role of the PPAR signaling pathway in HD, targets for treatment may be found not only for HD, but other polyglutamine diseases and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Transcription dysregulation and mitochondrial dysfunction have been individually linked to the development of multiple human diseases, including neurodegenerative diseases. This investigation will elucidate mechanisms of transcriptional dysregulation that underlie mitochondrial dysfunction to potentially facilitate design of therapeutic strategies to treat Huntington's Disease, and possibly other polyglutamine disorders and other neurodegenerative disorders, such as Parkinson's Disease. !